We investigated the temporal relationship between inflammation and cerebral atrophy in a longitudinal study of 19 relapsingremitting multiple sclerosis (RRMS) patients using serial monthly contrast enhanced MRI examinations and monthly measurements of brain fractional volume (BFV) for an average of 4 years. All RRMS patients had an active MRI scan at entry with a minimum of two new contrastenhancing lesions (CEL) over a minimum of 3 months during a baseline (pretreatment) scans. MRIs were evaluated while patients were treated with recombinant Interferon (IFN) and various other immunomodulatory agents. Monthly CEL and BFV were determined with cerebral atrophy was measured as percent brain fractional volume change (PBVC) compared to the entry baseline scan. The MS patients were separated into 2 groups based on response to IFN therapy. IFN responders (IFN R), had a >70% reduction in CEL during the first 20 months of treatment. Nonresponders (NR) showed no significant reduction in CEL compared to baseline and generally were treated with combination therapy. At entry, the mean BFV (0.884 0.02) of healthy control subjects was not significantly different from the mean BFV (0.882 0.02) in the MS cohort. The rate of cerebral atrophy as measured by percent decrease in BFVyear is 7fold higher in the MS group (0.73% year) compared healthy controls (0.1% yr), which is statistically significant (p 0.018). The relationship between cumulative CEL, and BFV on monthly MRI scans was determined by linear regression analysis and a relatively strong correlation was observed in individual patients. The correlation between CEL and BFV is significantly higher in the NR patients (R2 0.66) than in IFN R (R2 .0.19) p 0.00002. The results demonstrate that cerebral atrophy parallels that of contrast enhancing lesion accumulation. Immunomodulatory agents that effectively reduce CEL accumulation also slow the rate of atrophy.